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Deferasirox

Pronunciation

(de FER a sir ox)

Index Terms

  • ICL670

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Jadenu: 90 mg, 180 mg, 360 mg

Tablet Soluble, Oral:

Exjade: 125 mg, 250 mg, 500 mg

Brand Names: U.S.

  • Exjade
  • Jadenu

Pharmacologic Category

  • Chelating Agent

Pharmacology

Selectively binds iron, forming a complex that is excreted primarily through the feces.

Distribution

Adults: 14.4 ± 2.7L

Metabolism

Hepatic via glucuronidation by UGT1A1 (primarily) and UGT1A3; minor oxidation by CYP450; undergoes enterohepatic recirculation

Excretion

Feces (84%); urine (8%)

Clearance: Moderately lower (by 17.5%) in women than in men.

Time to Peak

Plasma: Tablets and tablets for oral suspension: ~1.5 to 4 hours

Half-Life Elimination

8 to 16 hours

Protein Binding

~99% to serum albumin

Special Populations: Renal Function Impairment

Patients with myelodysplastic syndromes (MDS) and CrCl 40 to 60 mL/minute had ~50% higher mean deferasirox trough levels compared to patients with MDS and CrCl >60 mL/minute.

Special Populations: Hepatic Function Impairment

Deferasirox exposure is increased. The average total (free and bound) AUC increased 16% in patients with mild (Child-Pugh class A) impairment and increased 76% in patients with moderate (Child-Pugh class B) impairment.

Special Populations: Children

In children 2 to <6 years of age, systemic exposure was ~50% lower than in adults.

Use: Labeled Indications

Chronic iron overload due to transfusions: Treatment of chronic iron overload caused by blood transfusions (transfusional hemosiderosis) in patients 2 years and older.

Chronic iron overload in nontransfusion-dependent thalassemia syndromes: Treatment of chronic iron overload in patients 10 years and older with nontransfusion-dependent thalassemia syndromes and with a liver iron concentration (LIC) of at least 5 mg of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L (US labeling) or serum ferritin consistently above 800 mcg/L (Canadian labeling).

Limitations of use: Safety and efficacy of deferasirox in combination with other iron chelation therapies have not been established. Controlled studies of deferasirox in myelodysplastic syndromes and chronic iron overload due to transfusions have not been conducted.

Contraindications

Known hypersensitivity to deferasirox or any component of the formulation; CrCl <40 mL/minute or serum creatinine >2 times the age-appropriate ULN; poor performance status; high-risk myelodysplastic syndromes; advanced malignancies; platelet counts <50,000/mm3

Canadian labeling: Additional contraindications (not in US labeling): MDS patients with <1 year life expectancy; CrCl <60 mL/minute

Dosing: Adult

Note: Calculate dose to the nearest whole tablet size.

Conversion from Exjade to Jadenu: The dose for Jadenu should be ~30% lower (rounded to the nearest whole tablet).

Chronic iron overload due to transfusions: Oral: Note: Treatment should only be initiated with evidence of chronic iron overload (ie, transfusion of ≥100 mL/kg of packed red blood cells [eg, ≥20 units for a 40 kg individual] and serum ferritin consistently >1,000 mcg/L).

US labeling:

Exjade:

Initial: 20 mg/kg once daily

Maintenance: Note: Consider interrupting therapy for serum ferritin <500 mcg/L (risk of toxicity may be increased). Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 5 or 10 mg/kg/day; titrate to individual response and treatment goals. In patients not adequately controlled with 30 mg/kg/day, doses up to 40 mg/kg/day may be considered for serum ferritin levels persistently >2,500 mcg/L and not decreasing over time (doses above 40 mg/kg/day are not recommended).

Jadenu:

Initial: 14 mg/kg once daily

Maintenance: Note: Consider interrupting therapy for serum ferritin <500 mcg/L (risk of toxicity may be increased). Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 3.5 or 7 mg/kg/day; titrate to individual response and treatment goals. In patients not adequately controlled with 21 mg/kg/day, doses up to 28 mg/kg/day may be considered for serum ferritin levels persistently >2,500 mcg/L and not decreasing over time (doses above 28 mg/kg/day are not recommended).

Canadian labeling: Dosing based on treatment goal and patient's individual transfusion rate:

Exjade:

Treatment goal: Maintenance of acceptable body iron levels:

Initial: 10 mg/kg once daily if transfused packed red blood cells (pRBCs) <7 mL/kg/month (approximately <2 units per month for an adult)

Initial: 20 mg/kg once daily if transfused pRBCs ≥7 mL/kg/month (approximately >2 units per month for an adult)

Treatment goal: Iron overload reduction:

Initial: 20 mg/kg once daily if transfused pRBCs <14 mL/kg/month (approximately <4 units per month for an adult)

Initial: 30 mg/kg once daily if transfused pRBCs ≥14 mL/kg/month (approximately >4 units per month for an adult)

Maintenance: Note: Consider interrupting therapy for serum ferritin <500 mcg/L (risk of toxicity may be increased).

Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 5 or 10 mg/kg/day; titrate to individual response and treatment goals. In patients with beta-thalassemia not adequately controlled with 30 mg/kg/day, doses up to 40 mg/kg/day may be considered. Do not exceed 30 mg/kg/day in non-beta-thalessemic patients.

Jadenu:

Treatment goal: Maintenance of acceptable body iron levels:

Initial: 7 mg/kg once daily if transfused packed red blood cells (pRBCs) <7 mL/kg/month (approximately <2 units per month for an adult)

Initial: 14 mg/kg once daily if transfused pRBCs ≥7 mL/kg/month (approximately >2 units per month for an adult)

Treatment goal: Iron overload reduction:

Initial: 14 mg/kg once daily if transfused pRBCs <14 mL/kg/month (approximately <4 units per month for an adult)

Initial: 21 mg/kg once daily if transfused pRBCs ≥14 mL/kg/month (approximately >4 units per month for an adult)

Maintenance: Note: Consider interrupting therapy for serum ferritin <500 mcg/L (risk of toxicity may be increased).

Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 3.5 or 7 mg/kg/day; titrate to individual response and treatment goals. In patients with beta-thalassemia not adequately controlled with 21 mg/kg/day, doses up to 28 mg/kg/day may be considered. Do not exceed 21 mg/kg/day in non-beta-thalessemic patients.

Chronic iron overload in non-transfusion-dependent thalassemia syndromes: Oral:

US labeling: Note: Treatment should only be initiated with evidence of chronic iron overload (hepatic iron concentration ≥5 mg Fe/g dry weight and serum ferritin >300 mcg/L).

Exjade:

Initial: 10 mg/kg once daily. Consider increasing to 20 mg/kg once daily after 4 weeks if baseline hepatic iron concentration is >15 mg Fe/g dry weight.

Maintenance: Monitor serum ferritin monthly; if serum ferritin is <300 mcg/L, interrupt therapy and obtain hepatic iron concentration. Monitor hepatic iron concentration every 6 months; interrupt therapy if hepatic iron concentration <3 mg Fe/g dry weight. After 6 months of therapy, consider dose adjustment to a maximum of 20 mg/kg/day if hepatic iron concentration >7 mg Fe/g dry weight. Reduce dose to ≤10 mg/kg when hepatic iron concentration is 3 to 7 mg Fe/g dry weight. Do not exceed 20 mg/kg/day. After interruption, resume treatment when hepatic iron concentration >5 mg Fe/g dry weight.

Jadenu:

Initial: 7 mg/kg once daily. Consider increasing to 14 mg/kg once daily after 4 weeks if baseline hepatic iron concentration is >15 mg Fe/g dry weight.

Maintenance: Monitor serum ferritin monthly; if serum ferritin is <300 mcg/L, interrupt therapy and obtain hepatic iron concentration. Monitor hepatic iron concentration every 6 months; interrupt therapy if hepatic iron concentration <3 mg Fe/g dry weight. After 6 months of therapy, consider dose adjustment to a maximum of 14 mg/kg/day if hepatic iron concentration >7 mg Fe/g dry weight. Reduce dose to ≤7 mg/kg when hepatic iron concentration is 3 to7 mg Fe/g dry weight. Do not exceed 14 mg/kg/day. After interruption, resume treatment when hepatic iron concentration >5 mg Fe/g dry weight.

Canadian labeling: Note: Treatment should only be initiated with evidence of chronic iron overload (hepatic iron concentration ≥5 mg Fe/g dry weight and serum ferritin consistently >800 mcg/L).

Exjade:

Initial: 10 mg/kg/day

Maintenance: Do not exceed 10 mg/kg/day in patients whose hepatic iron concentration was not evaluated and if serum ferritin ≤2,000 mcg/L. Monitor serum ferritin monthly; consider dose adjustment by 5 or 10 mg/kg/day every 3 to 6 months if hepatic iron concentration ≥7 mg Fe/g dry weight or serum transferrin levels consistently >2,000 mcg/L. Patients receiving >10 mg/kg should have their dose reduced to ≤10 mg/kg when hepatic iron concentration <7 mg Fe/g dry weight or serum ferritin <2,000 mcg/L. Interrupt therapy when hepatic iron concentration <3 mg Fe/g dry weight or serum ferritin <300 mcg/L. Doses above 20 mg/kg/day are not recommended.

Jadenu:

Initial: 7 mg/kg/day

Maintenance: Do not exceed 7 mg/kg/day in patients whose hepatic iron concentration was not evaluated and if serum ferritin ≤2,000 mcg/L. Monitor serum ferritin monthly; consider dose adjustment by 3.5 to 7 mg/kg/day every 3 to 6 months if hepatic iron concentration ≥7 mg Fe/g dry weight or serum transferrin levels consistently >2,000 mcg/L and not showing downward trend, and if tolerating therapy well. Doses >14 mg/kg/day are not recommended (has not been studied). Patients receiving >10 mg/kg should have their dose reduced to ≤7 mg/kg when hepatic iron concentration <7 mg Fe/g dry weight or serum ferritin ≤2,000 mcg/L. Interrupt therapy when hepatic iron concentration <3 mg Fe/g dry weight or serum ferritin <300 mcg/L. After interruption, treatment may be resumed when there is evidence of iron overload.

Dosage adjustment with concomitant medications:

US labeling: Bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol) or potent UGT inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Avoid concomitant use; if coadministration necessary, consider increasing the initial dose of deferasirox dose by 50%; monitor serum ferritin and clinical response.

Canadian labeling: Potent UGT inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): There are no specific dosage adjustments provided in the manufacturer’s labeling; however, if coadministration is necessary, the manufacturer recommends to consider increasing deferasirox dose per clinical response.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Calculate dose to the nearest whole tablet size. When calculating dose, consider changes in weight over time.

Chronic iron overload due to transfusions: Children ≥2 years and Adolescents: Refer to adult dosing.

Chronic iron overload in non-transfusion-dependent thalassemia syndromes: Children ≥10 years and Adolescents: Refer to adult dosing.

Conversion from Exjade to Jadenu: The dose for Jadenu should be ~30% lower (rounded to the nearest whole tablet).

Dosing: Renal Impairment

CrCl should be estimated using the Cockcroft-Gault formula.

Renal impairment at treatment initiation:

US labeling:

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 40 to 60 mL/minute: Reduce initial dose by 50%.

CrCl <40 mL/minute or serum creatinine >2 times age-appropriate ULN: Use is contraindicated.

Canadian labeling:

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl <60 mL/minute or serum creatinine >2 times age-appropriate ULN: Use is contraindicated.

Renal toxicity during treatment:

US labeling:

Transfusional iron overload:

Adolescents ≥16 years and Adults: For increase in serum creatinine ≥33% above the average baseline, repeat within 1 week; if still elevated by ≥33%: Reduce daily dose by 10 mg/kg (for Exjade) or 7 mg/kg (for Jadenu)

Children ≥2 years to Adolescents 15 years: For increase in serum creatinine >33% above the average baseline level and above the age-appropriate ULN: Reduce daily dose by 10 mg/kg (for Exjade) or 7 mg/kg (for Jadenu)

All patients: CrCl <40 mL/minute or serum creatinine >2 times age-appropriate ULN: Discontinue treatment.

Non-transfusion-dependent thalassemia syndromes:

Adolescents ≥16 years and Adults: For increase in serum creatinine ≥33% above the average baseline, repeat within 1 week; if still elevated by ≥33%:

Exjade: Interrupt therapy if the dose is 5 mg/kg; reduce dose by 50% if the dose is 10 or 20 mg/kg

Jadenu: Interrupt therapy if the dose is 3.5 mg/kg; reduce dose by 50% if the dose is 7 or 14 mg/kg

Children ≥10 years to Adolescents 15 years: For increase in serum creatinine >33% above the average baseline level and above the age-appropriate ULN: Reduce daily dose by 5 mg/kg (for Exjade) or 3.5 mg/kg (for Jadenu)

All patients: CrCl <40 mL/minute or serum creatinine >2 times age-appropriate ULN: Discontinue treatment.

Canadian labeling:

Adolescents ≥16 years and Adults: For increase in serum creatinine >33% above the average pretreatment level for 2 consecutive weekly levels, reduce daily dose by 10 mg/kg (for Exjade) or 7 mg/kg (for Jadenu).

Children ≥2 years and Adolescents <16 years: For increase in serum creatinine above the age-appropriate ULN for 2 consecutive levels, reduce daily dose by 10 mg/kg (for Exjade) or 7 mg/kg (for Jadenu).

All patients: Progressive increase serum creatinine beyond ULN: Withhold treatment.

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary; monitor closely for efficacy and for adverse reactions requiring dosage reduction.

Moderate impairment (Child-Pugh class B): Initial: Reduce dose by 50%; monitor closely for efficacy and for adverse reactions requiring dosage reduction.

Severe impairment (Child-Pugh class C): Avoid use.

Hepatic toxicity during treatment: Severe or persistent increases in transaminases/bilirubin: Reduce dose or temporarily interrupt treatment.

Dosing: Adjustment for Toxicity

Bone marrow suppression: Interrupt treatment; may reinitiate once cause of cytopenia has been determined; use contraindicated if platelet count <50,000/mm3

Dermatologic toxicity:

Rash (severe): Interrupt treatment; may reintroduce at a lower dose (with future dose escalation) and short-term oral corticosteroids.

Severe skin reaction (Stevens-Johnson syndrome, erythema multiforme): Discontinue and evaluate.

Gastrointestinal: Discontinue treatment for suspected GI ulceration or hemorrhage.

Hearing loss or visual disturbance: Consider dose reduction or treatment interruption.

Administration

Oral:

Tablets (Jadenu): Swallow with water or other liquids at the same time each day. Administer on an empty stomach or with a light meal (contains less than 7% fat content and ~250 calories). For patients who have difficulty swallowing whole tablets, may crush tablets and mix with soft foods (eg, yogurt, applesauce); consume entire mixture immediately after preparation (do not store for future use). Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet.

Tablets for suspension (Exjade): Administer tablets by making an oral suspension; do not chew or swallow tablets whole. Completely disperse tablets in water, orange juice, or apple juice (use 3.5 ounces for total doses <1 g; 7 ounces for doses ≥1 g); stir to form a fine suspension and drink entire contents. Rinse remaining residue with more fluid; drink. Avoid dispersion of tablets in milk (due to slowed dissolution) or carbonated drinks (due to foaming) (Séchaud, 2008). Administer at same time each day on an empty stomach, at least 30 minutes before food. Do not take simultaneously with aluminum-containing antacids.

Do not take simultaneously with aluminum-containing antacids.

Dietary Considerations

Tablets for oral suspension: Bioavailability increased variably when taken with food; take on empty stomach 30 minutes before a meal.

Tablets: Bioavailability decreased slightly (not clinically meaningful) after a low-fat meal and increased after a high fat meal; take on an empty stomach or with a light meal (containing ~250 calories and <7% fat content).

Storage

Store at 25°C (77°F); excursions permitted to 15°C and 30°C (59°F and 86°F). Protect from moisture.

Drug Interactions

Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy

Aluminum Hydroxide: May diminish the therapeutic effect of Deferasirox. Avoid combination

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Anticoagulants: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Bile Acid Sequestrants: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Bisphosphonate Derivatives: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Corticosteroids: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Exceptions: Beclomethasone (Nasal); Budesonide (Nasal); Ciclesonide (Nasal); Desonide; Dexamethasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Fluocinolone (Ophthalmic); Fluticasone (Nasal); Loteprednol; Mometasone (Nasal); PrednisoLONE (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

CYP1A2 Substrates: Deferasirox may increase the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP2C8 Substrates: Deferasirox may increase the serum concentration of CYP2C8 Substrates. Monitor therapy

CYP3A4 Substrates: Deferasirox may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

PHENobarbital: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Phenytoin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). Consider therapy modification

Repaglinide: Deferasirox may increase the serum concentration of Repaglinide. Monitor therapy

RifAMPin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Ritonavir: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Theophylline: Deferasirox may increase the serum concentration of Theophylline. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Avoid combination

Adverse Reactions

>10%:

Dermatologic: Skin rash (dose related; 2% to 11%)

Gastrointestinal: Abdominal pain (dose related; 21% to 28%), nausea (dose related; 2% to 23%), vomiting (dose related; 10% to 21%), diarrhea (dose related; 5% to 20%)

Genitourinary: Proteinuria (19%)

Renal: Increased serum creatinine (dose related; 2% to 38%)

1% to 10%:

Central nervous system: Fatigue (≤1%)

Hepatic: Increased serum ALT (2% to 8%)

Respiratory: Pharyngolaryngeal pain (≤1%)

Frequency not defined:

Central nervous system: Headache (Phatak 2010; Vichinsky 2007)

Gastrointestinal: Constipation (Vichinsky 2007)

Hepatic: Increased serum bilirubin (Vichinsky 2007)

Infection: Viral infection (Vichinsky 2007)

Neuromuscular & skeletal: Arthralgia (Vichinsky 2007), back pain (Vichinsky 2007)

Respiratory: Cough (Vichinsky 2007), nasopharyngitis (Vichinsky 2007), pharyngitis (Vichinsky 2007), respiratory tract infection (Vichinsky 2007)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acute renal failure, agranulocytosis, alopecia, anaphylaxis, anemia (worsening), cataract, cholelithiasis, cytopenia, drug fever, duodenal ulcer, dyschromia, edema, erythema multiforme, Fanconi’s syndrome, gastric ulcer, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, glycosuria, hearing loss (including high frequency), hematuria, fever, hepatic failure, hepatic insufficiency, hepatitis, hyperactivity, hypersensitivity angiitis, hypersensitivity reaction, hypocalcemia, IgA vasculitis, increased intraocular pressure, interstitial nephritis, maculopathy, neutropenia, nontuberculous mycobacterial infection, optic neuritis, pancreatitis (associated with gallstones), purpura, renal tubular disease, renal tubular necrosis, retinopathy, sleep disorder, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, visual disturbance

ALERT: U.S. Boxed Warning

Renal failure:

Deferasirox can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Measure serum creatinine and determine creatinine clearance (CrCl) in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter. For patients with baseline renal impairment or at increased risk of acute renal failure, monitor creatinine weekly for the first month, and then at least monthly. Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine.

Hepatic failure:

Deferasirox can cause hepatic injury, including hepatic failure and death. Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter. Avoid use of deferasirox in patients with severe (Child-Pugh class C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh class B) hepatic impairment.

Gastrointestinal events:

Deferasirox can cause GI hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts. Monitor patients and discontinue deferasirox for suspected GI ulceration or hemorrhage.

Warnings/Precautions

Concerns related to adverse effects:

• Auditory disturbances: Decreased hearing and high-frequency hearing loss have been reported (rare) with use; perform auditory testing prior to initiation and regularly (every 12 months) during use; if abnormalities develop, monitor more closely and consider dose reduction or treatment interruption.

• Bone marrow suppression: Cytopenias (including agranulocytosis, neutropenia, thrombocytopenia, and worsening anemia) have been reported (some fatal); risk may be increased in patients with preexisting hematologic disorders; monitor blood counts regularly. Interrupt treatment in patients who develop cytopenias; may reinitiate once cause of cytopenia has been determined; use contraindicated if platelet count <50,000/mm3.

• Dermatologic toxicity: May cause skin rash (dose-related); mild to moderate rashes may resolve without treatment interruption; for severe rash, interrupt and consider restarting at a lower dose with dose escalation and oral steroids. Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have also been reported; if suspected, discontinue immediately and evaluate. Do not reintroduce therapy.

• Gastrointestinal events: [US Boxed Warning]: Gastrointestinal (GI) hemorrhage (including fatalities) may occur; observed more frequently in elderly patients with advanced hematologic malignancies and/or low platelet counts; discontinue treatment for suspected GI hemorrhage or ulceration. Other GI effects including irritation and ulceration (sometimes complicated with GI perforation, including fatalities) have been reported. Use caution with concurrent medications that may increase risk of adverse GI effects (eg, NSAIDs, corticosteroids, anticoagulants, oral bisphosphonates). Monitor patients closely for signs/symptoms of GI ulceration/bleeding.

• Hepatic failure: [US Boxed Warning]: Hepatic injury and failure (including fatalities) may occur. Monitor transaminases and bilirubin at baseline, every 2 weeks for 1 month, then at least monthly thereafter. Hepatitis and elevated transaminases have also been reported. Hepatotoxicity is more common in patients >55 years of age and in patients with significant comorbidities (eg, cirrhosis, multiorgan failure). Reduce dose or temporarily interrupt treatment for severe or persistent increases in transaminases/bilirubin. [US Boxed Warning]: Avoid use in patients with severe (Child-Pugh class C) hepatic impairment; a dose reduction is required in patients with moderate (Child-Pugh class B) hepatic impairment. Monitor patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) impairment closely for efficacy and for adverse reactions requiring dosage reduction.

• Hypersensitivity: Hypersensitivity reactions, including severe reactions (anaphylaxis and angioedema) have been reported; onset is usually within the first month of treatment. Discontinue if severe.

• Ocular disturbances: Lens opacities, cataracts, intraocular pressure elevation, and retinal disorders have been reported (rare) with use; perform ophthalmic testing prior to initiation and regularly (every 12 months) during use; if abnormalities develop, monitor more closely and consider dose reduction or treatment interruption.

• Renal failure: [US Boxed Warning]: Acute renal failure (including fatalities and cases requiring dialysis) may occur; observed more frequently in patients with comorbid conditions and advanced hematologic malignancies. Obtain serum creatinine and calculate creatinine clearance (CrCl) in duplicate at baseline prior to initiation, and monitor at least monthly thereafter; in patients with underlying renal dysfunction or at risk for acute renal failure, monitor creatinine weekly during the first month then at least monthly thereafter. Dose reduction, interruption, or discontinuation should be considered for serum creatinine elevations. Monitor serum creatinine and/or CrCl more frequently if creatinine levels are increasing. May cause proteinuria; monitor monthly although the clinical significance of proteinuria is unknown. Renal tubular damage, including Fanconi syndrome, has also been reported, primarily in pediatric/adolescent patients with beta-thalassemia and serum ferritin levels <1,500 mcg/L. Use with caution. Dosage modification or treatment discontinuation may be required; reductions in initial dose are recommended for patients with CrCl 40 to 60 mL/minute; use is contraindicated in patients with a CrCl <40 mL/minute (US labeling) or <60 mL/minute (Canadian labeling) or serum creatinine >2 times age-appropriate ULN.

Disease-related concerns:

• Heart failure: The Canadian labeling recommends against use in patients with acute heart failure associated with iron overload (has not been studied).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution due to the higher incidence of toxicity (eg, hepatotoxicity) and fatal events during use; monitor elderly patients closely.

Dosage form specific issues:

• Lactose: May contain lactose; Exjade Canadian product labeling recommends avoiding use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndromes.

Other warnings/precautions:

• Appropriate use: For transfusion-related iron overload, treatment should be initiated with evidence of chronic iron overload (ie, transfusion of ≥100 mL/kg of packed RBCs [eg, ≥20 units for a 40 kg individual] and serum ferritin consistently >1,000 mcg/L). For non-transfusion-dependent iron overload, initiate with liver iron concentration ≥5 mg Fe/g dry liver weight, and serum ferritin >300 mcg/L. Prior to use, consider risk versus anticipated benefit with respect to individual patient’s life expectancy, prognosis, and comorbidities. An improvement in survival or disease-related symptoms due to the therapy has not been established in clinical trials. Postmarketing experience indicates serious reactions, including fatalities, have occurred with deferasirox use, particularly when used in older patients with comorbidities or advanced disease.

• Other minerals: Deferasirox has a low affinity for binding with zinc and copper, may cause variable decreases in the serum concentration of these trace minerals.

• Overchelation: Overchelation of iron may increase development of toxicity; monitor sodium ferritin; consider temporary interruption of treatment in transfusional iron overload when serum ferritin <500 mcg/L; in non-transfusion-dependent thalassemia when serum ferritin <300 mcg/L or hepatic iron concentration <3 mg Fe/g dry weight.

Monitoring Parameters

Serum ferritin (baseline, monthly thereafter), iron levels (baseline), CBC with differential, serum creatinine, and CrCl (2 baseline assessments then monthly thereafter; in patients who are at increased risk of complications [eg, preexisting renal conditions, elderly, comorbid conditions, or receiving other potentially nephrotoxic medications]: weekly for the first month then at least monthly thereafter); hepatic iron concentration (non-transfusion-dependent thalassemia; baseline, every 6 months); urine protein (monthly); monitor serum creatinine and/or CrCl more frequently if creatinine levels are increasing; serum transaminases (ALT/AST) and bilirubin (baseline, every 2 weeks for the first month, then monthly); baseline and annual auditory and ophthalmic examination (including slit lamp examinations and dilated fundoscopy); performance status (in patients with hematologic malignancies); signs/symptoms of GI ulcers or hemorrhage; cumulative number of RBC units received

Canadian labeling also recommends monitoring growth and body weight every 12 months in pediatric patients.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to the use of deferasirox in pregnant women is limited (Vini 2011). The Canadian labeling recommends that deferasirox not be used during pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of abdominal ulcers (very bad stomach or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or swelling that is not normal), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of infection, severe nausea, vomiting, severe diarrhea, hearing impairment, hearing loss, vision changes, severe dyspepsia, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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